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Hepatic and renal sat-1 and CFEX expression in ethylene glycol-induced oxalate nephrolithiasis in rats

Background: The epidemiological incidence of oxalate nephrolithiasis is higher in men than in women. Oxalate is predominantly produced in the liver and then released into the systemic circulation by sat1, a sulfate anion transporter, which is localized in the sinusoidal membrane of hepatocytes, where it mediates exit of oxalate in exchange for sulfate. In renal proximal tubules, sat1 is responsible for basolateral uptake of oxalate into the cell and release of sulfate into systemic circulation. Finally, oxalate is extruded into the urine by the luminal chloride-formate exchanger, CFEX, which also accepts oxalate as a substrate. Methods: The model of ethylene glycol (EG)-induced oxalate nephrolithiasis in adult male and female rats was used to monitor changes in sat1, CFEX, and the rate-limiting enzymes of oxalate synthesis, alcohol dehydrogenase (Adh1) and hydroxy acid oxidase (Hao1). Protein and mRNA expression was studied by immunochemistry and real time RT-PCR. Results: As compared to controls, EG-treated animals exhibited higher concentrations of oxalate in plasma and urine, and a higher abundance of oxalate crystals in urine with male dominance. Sat1 protein in liver and kidneys was male-dominant in controls, increased only in EG-treated female rats, while sat1 mRNA stayed unchanged. CFEX mRNA in both organs was sex-independent and unaffected by EG treatment. Adh1 and Hao1 mRNA in both organs exhibited distinct sex dependency which remained unchanged upon EG treatment. A general male-dominant Hao1 expression in kidneys of untreated rats was also shown by microarray analysis. Conclusions: In conclusion, despite hyperoxaluria in EG-treated animals, the expression of sat1 in males and of CFEX in both sexes was sufficient to handle the EG-induced production and secretion of oxalate.

oxalate stones; urolithiasis; rat kidney; rat liver; immunocytochemistry; membrane transporters; protein expression; mRNA expression

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